PDB is an ancient disease, claimed to be identified in a Neanderthal skull;

• Is a common disease (5% prevalence in UK) but most are asymptomatic.
• Primarily a disorder of increased osteoclastic resorption with secondary stimulation of osteoblasts.
  • Pathophysiology: In Paget's disease, the osteoclasts look 'bizzare' on histology AND they have increased sensitivity to vitamin D.
  • Pathogenesis incompletely understood.
  • #autosomalDominant with incomplete penetrance.
• Commoner in older males (onset usually after 55)
  • Thickening of skull bones. -> can lead to hearing loss, increase in hat size
    • Cotton wool appearance on skull X ray.
    • Increased uptake at lesions is seen on bone scintigraphy.
    • Calcium and phophate are normal
    • Bone: Fractures, Bone sarcoma, Deafness (cranial nerve entrapment)

Blackwater fever is a rare complication of malaria which can be fatal. It is caused by large intravascular haemolysis resulting in haemoglobinuria, anaemia, jaundice and acute kidney injury. Urine is classically black or dark red in colour.The cause of the massive haemolysis is unknown. The treatment is with antimalarials, intravenous fluids and in some cases dialysis. Urinalysis reveals blood which is not seen on microscopy as it is haemoglobinuria.
[!INFO] AKA Bilharziasis
after the name of the disoverer

• Parasitic infection by a trematode (Phylum platyhelminthes)

• Complex life cycle : snails -> intermediate host; human -> definitive host.

• 3 or 4 Species of parasites.

  • S. mansoni and S. japonicum cause intestinal tract disease
  • S. haematobium causes genitourinary tract disease

• After skin penetration the worms migrate to the liver.

  • Then haematobium species lays eggs in the paravesical venous plexus -> eggs migrate to bladder -> haematuria
  • Mansoni and japonicum lay eggs in the mesenteric veins -> eggs migrate to intestinal lumen -> diarrhoea

• Infective stages are excreted via urine and faeces.

[!TIP] Mnemonic for the species:

• Haematobium -> haematuria
• Mansoni -> mesenteric veins -> diarrhoea

• Acute infection : seen in travellers; locals can have low level parasitaemia

  • Acute infection can present with "swimmer's itch" (acute itch after swimming + localized dermatitis - when parasite enters the skin) and/or acute schistosomiasis syndrome (Katayama syndrome), a systemic hypersensitivity reaction to schistosome antigens and circulating immune complexes. (See 'Acute infection' above.)

• Chronic infection - GI - GI ulceration and scarring + blood loss; liver fibrosis and oesophageal varices .

• Diagnosis : urine culture and microscopy,

  • S. haematobium eggs can be demonstrated in urine.
  • Eosinophilia

[!INFO] In general
G protein coupled: regulate slow processes

Eg: Muscarinic

Ligand gated ion channels : fast processes (like neurotranmission)

Eg: GABA, Glutamate, Nicotinic

Mnemonic: MG (myasthenia gravis ) Muscarinic -> G protein, Nicotinic -> ligand gated.

Enzyme linked receptors

Receptor tyrosine kinases are the commonest type of enzyme linked receptors.

Enzyme linked receptors are receptors which

• either have intrinsic kinase enzyme activity which is stimulated by ligand binding (eg: "receptor tyrosine kinases" like the insulin receptor) (groups 1 and 2 below)
• are act via cytoplasmic kinase enzymes (group 3)

 3 Main Types of Enzyme-Linked Receptors

1. Receptor Tyrosine Kinases [RTK] • make up the majority of enzyme-linked receptors.

   • Signal transduction through RTK results in specific phosphorylation of tyrosine residues on target proteins and subsequent increase in gene transcription and regulation of cell growth, differentiation and survival.

2. Serine/Threonine Kinases •

   • specifically phosphorylate the hydroxyl side chains of serine or threonine amino acid residues. These kinases may have a role in cell proliferation, differentiation, apoptosis and even embryonic development.

3. Tyrosine Kinase-Associated Receptors [“mixed”] • do not have a tyrosine kinase domain, rather act through cytoplasmic tyrosine kinases.

Mechanism of transduction

1. Ligand binding leads to dimerization of two neighboring receptors.
2. Neighboring dimerized receptors auto phosphorylate one another
3. SH2-domain proteins bind to the phosphorylated receptors and are then phosphorylated enabling the continuation of the signal eventually leading to gene transcription.

• SH2-domain [Scr homology 2] • protein domain composed of about 100 amino acid residues. SH2-domains most commonly play a role in the signal transduction by receptor tyrosine kinase pathways as you will see later on in this section. They interact with specific target molecules (peptides) with a phosphorylated tyrosine residue.
• For example, PI3K is a protein with an SH2 domain. This molecule is involved in the insulin transduction pathway.

Tyrosine kinases

Spondyloarthritis (SpA)

• radiographic changes in the sacroiliac joints in patients with axial SpA
• and asymmetric (oligo)arthritis, heel enthesitis and dactylitis in patients with peripheral SpA
• Rheumatoid factors negative. (<- Seronegative arthropathies)

Inflammatory osteoproliferative lesions in the spine are called syndesmophytes (marginal and non-marginal), and degenerative osteoproliferative lesions are called osteophytes. Syndesmophytes are more vertically oriented than osteophytes.

[!TIP] Mnemonic: RePsAnkIb

• Reactive
• Psoriatic
• Anky spondylos
• IBD associated

Ankylosing = stiffness or fixation of a joint by disease

- Advanced cases: fusion of the sacroiliac joints, and bamboo spine. (Gadolinum MRI is more sensitive than Xray at detecting early changes).

Diagnosis

"Plain x-ray of the sacroiliac joints is the most useful investigation in establishing the diagnosis."

• sacroiliitis is usually the first manifestation 5 and is symmetrical and bilateral
  • the sacroiliac joints first widen before they narrow
  • subchondral erosions, sclerosis, and proliferation on the iliac side of the SI joints
  • at end-stage, the SI joint may be seen as a thin line or not visible

The sacroiliac joint is actually a synovial joint with hyaline on the sacral surface and fibrous cartilage on the iliac surface Source.

• Prevention of syndesmophyte formation -> early diagnosis and initiation of exercise regimen.
• TNF-α blockers - etanercept and adalimumab provide HUGE symptomatic relief. They reduced morbidity

Bone changes seen in various diseases

• Acute, asymmetrical, lower limb oligoarthritis days to weeks after infection such as dysentery or some sexually acquired infections.
  • keratoderma blennorhagica - raised red plaques and pustules. Can occur on soles
  • 
• Majority of patients recover in 6 months but 30% develop chronic symptoms.
• Management is symptomatic. (NSAIDS, corticosteroids, DMARDS like sulfasalazine and infliximab if NSAIDS don't work or a contraindicated)

Langerhans cell histiocytosis

• A multisystem disease
• Birbeck granules present on EM: They have a "tennis racket" shape.
• More common in children (1-3 years of age) but can present in any age even in adults.
• Is one cause of interstitial lung disease.
• Adults presents with pulmonary involvement.
• The disease involves the formation of multiple granulomas throughout the body.
• Adults commonly have lytic lesions in the jaw and skull.
• Pulmonary involvement: also commoner in adults. non productive cough, spontaneous pneumothorax, chest pain etc.
• Upper and middle zone involvement is characteristic.
  Other features:
• bone pain, typically in the skull or proximal femur
• cutaneous nodules
• recurrent otitis media/mastoiditis